PROJECT SUMMARY The candidate is a dual-trained periodontist scientist who is committed to an academic career dedicated to study periodontal disease and improve oral health. Periodontitis is a polygenetic, inflammatory response towards bacterial pathogens at the gingival surface and affects 47% of the adult population in the United States. This common oral disease, without effective management, eventually leads to tooth loss and is significantly associated with systemic conditions such as diabetes. Analysis of a Genome Wide Association Study (GWAS) for periodontitis has identified Tumor necrosis factor Receptor-Associated Factor 3 Interacting Protein 2 (TRAF3IP2) as a target gene of interest. TRAF3IP2 dysfunction, such as induced by key genetic variants, is significantly associated with a periodontal inflammation phenotype defined by a high pathogen burden in plaque and local inflammation.TRAF3IP2 is a non-redundant adaptor molecule in the IL-17 pathway, which plays a critical role in mucosal defense. The objective of this research proposal is to acquire knowledge of the TRAF3IP2-mediated IL-17 response in gingival barrier defense mechanisms and the variant-induced functional defects in the IL-17 pathway. The candidate hypothesizes that loss of TRAF3IP2-IL17 signaling compromises the oral epithelial barrier and mucosal inflammatory signature and promotes dysbiotic microbiome overgrowth. This hypothesis will be tested by both in vitro and in vivo genetic approaches. Using Traf3ip2 ablated mice, the candidate will first determine the role of the IL-17/TRAF3IP2 pathway-modulated immune response and microbial community structure in a periodontal pathogen-induced murine alveolar bone loss model (Aim1). The candidate will then investigate the role of the IL-17/TRAF3IP2 pathway in mucosal physical barrier function and mechanism of IL-17-regulated tight junction structure (Aim 2). The candidate will further determine the TRAF3IP2 variant effect on immune response as reflected by the transcriptional and post-transcriptional regulation of chemokine synthesis and barrier function in genetically engineered, human gingival epithelial cells (Aim 3). The implementation of this research proposal requires additional training including complex microbial community structure analysis, Th17/IL-17 immunobiology, epithelial biology and molecular genomics. Strong mentorship by experts in each field and the exceptional environment at the University of North Carolina at Chapel Hill will foster the accomplishment of this research proposal and expedite the career development of the candidate. The scientific component and training outlined in this proposal provide a pathway to achieving not only the candidate's short-term goal, which is to transition into an independent investigator at a tenure track faculty position with R01 funding support, but also the long-term goal, which is to update understanding of host-pathogen interactions at the mucosal surface. The expertise gained will facilitate the development of novel preventive, diagnostic and therapeutic means to tackle periodontal disease and improve oral health.